DESCRIPTION (Adapted from applicants abstract): Aging results in a decline in immune vigor with the most significant changes occurring in the T cell compartment. It is frequently suggested that the diminution in peripheral T cell activity is the result of thymic involution, a very early event in the immunosenescence process, which is characterized by the loss of lymphoid cells and the diminished emigration of mature T cells to the periphery. The first specific aim of the proposed experimentation is to examine in depth the maturation of T cells in the aged thymus. Intrathymic T cell maturation is now recognized to be a complex, multi-step process in which bone-marrow derived pro-thymocytes seed the thymus. Here the pro-thymocyte undergoes expansion and sequential expression of Thy, T cell receptors, and the CD4 and CD8 markers. It has previously been established that; aged bone marrow pro- thymocytes are competent to seed a thymic rudiment, and that while the aged thymus can accept pro-thymocytes, the aged thymus does not support vigorous thymocyte proliferation. It is hypothesized that specific steps of intrathymic T cell differentiation are aging-"sensitive" occurring with diminished efficiency in aged individuals, which ultimately results in diminished T cell emigration. Although there is a significant decline in naive T cell emigration from the thymus with advancing age, the size of the peripheral T lymphocyte compartment remains relatively constant. This suggests that peripheral expansion or self renewal play important roles in maintaining T cell homeostasis. The second specific aim is to examine these aspects of T cell biology to determine how aging affects the lifespan of memory and naive CD4+ and CD8+ T cells, the expansion potential of these subsets, and their self-renewal capacity. The ability to distinguish memory and naive T cells on the basis of surface marker expression necessitates a re-examination of older studies and may resolve conflicting data regarding the "lifespan" of memory and naive cells in the aged animal. It is anticipated that the results shall advance our understanding of the consequences of aging on T cell differentiation and the peripheral T cell compartment allowing the design of more effective means of manipulating the immune system to achieve protective immunity in the aged population.